Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease affecting motor neurons of the anterior horn and brainstem and caused by the expansion of a polyglutamine tract within the androgen receptor (AR). Recent findings have shown that the disease is initiated by the binding of the AR to its ligand, testosterone or dihydrotestosterone, and its subsequent translocation to the nucleus. This result suggests that the manipulation of the AR ligand, and/or it's binding to the AR, is an important target for therapeutic intervention. Testosterone is metabolized to a more potent form, dihydrotestosterone (DHT), by the enzyme 5-alpha reductase. The neuronal cell type differences in the expression of this enzyme suggest that 5-alpha reductase expression in the motor neurons of the anterior hom and brainstem may contribute to the cell type specificity of SBMA. We propose to test the hypothesis that 5-alpha reductase expression contributes to disease pathogenesis and cell type specificity by modulating its function, using genetic and pharmacologic approaches. Lastly, recent studies indicate that the function of the AR in its normal capacity as a transcription factor is unnecessary for disease pathogenesis, suggesting that nuclear translocation alone is responsible for the onset of disease. We propose to test this hypothesis through the genetic manipulation of AR nuclear translocation in both cell and mouse models of SBMA. Since polyglutamine expansion has been shown to alter the catabolism of the mutant AR, the effect of subcellular localization on AR catabolism of the AR, as well as on its phosphorylation state will be investigated. [unreadable] [unreadable]